Therapeutic Class Overview Fluoroquinolones

INTRODUCTION  The fluoroquinolones are broad-spectrum antibiotics grouped into generations based on their spectrum of activity (Bolon, 2011). ○ First generation agents, which are structurally quinolones rather than fluoroquinolones, possess activity against aerobic gram-negative bacteria but are not effective against aerobic gram-positive bacteria or anaerobes. . The first generation agents (eg, nalidixic acid, cinoxacin) are no longer on the market. ○ Second generation agents, the original fluoroquinolones, contain a fluorine atom at position C-6. These agents offer improved coverage against gram-negative bacteria and moderately improved gram-positive coverage. . The available second generation fluoroquinolones include ciprofloxacin, levofloxacin, and ofloxacin. Lomefloxacin and norfloxacin are second generation agents which are no longer on the market. ○ Third generation agents achieve greater potency against gram-positive bacteria, particularly pneumococci, and also possess good activity against anaerobes. . All three of the third generation agents, gatifloxacin, grepafloxacin, and sparfloxacin, were removed from the market due to toxicities. ○ Fourth generation fluoroquinolones have superior coverage against pneumococci and anaerobes. These agents include moxifloxacin and gemifloxacin. One additional agent, trovafloxacin, was removed from the market due to toxicities. ○ The most recently approved fluoroquinolone, delafloxacin, has an even broader spectrum of antibiotic activity and is commonly referred to as a “next generation” fluoroquinolone.  The fluoroquinolones have been used to treat a variety of infections including urinary tract infections, sinusitis, lower respiratory tract infections, intra-abdominal infections, infectious diarrhea, skin and skin structure infections, sexually transmitted diseases, and bacterial prostatitis. A few of the agents also have Food and Drug Administration (FDA) approval for inhalational anthrax and plague. There is also considerable off-label data for use in neutropenic patients and for treatment of tuberculosis and mycobacteria infections in patients with human immunodeficiency virus (HIV). Due to the boxed warning for disabling and potentially irreversible serious adverse reactions involving the tendons, muscles, joints, nerves, and central nervous system, fluoroquinolones should be reserved for patients with no other treatment options when used to treat acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections (FDA press release, 2016).  As with all antibiotics, local resistance patterns should be considered when prescribing these agents.  Ciprofloxacin, delafloxacin, levofloxacin, and moxifloxacin are available as intravenous and oral formulations. Ciprofloxacin, levofloxacin, moxifloxacin, and ofloxacin are available in otic and/or ophthalmic formulations. Only the oral formulations and indications will be included in this review.  Medispan class: Fluoroquinolones

Table 1. Medications Included Within Class Review Drug Generic Availability Avelox (moxifloxacin)  Baxdela (delafloxacin) - Cipro (ciprofloxacin)  ciprofloxacin extended release*  Factive (gemifloxacin) - Levaquin (levofloxacin)  ofloxacin†  * The branded product, Cipro XR, is no longer marketed. † The branded product, Floxin, is no longer marketed. (Drugs@FDA, 2017; Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, 2017)

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INDICATIONS Table 2. Food and Drug Administration Approved Indications

Indication Cipro Avelox release Factive Levaquin Levaquin ofloxacin extended extended BAXDELA BAXDELA ciprofloxacin ciprofloxacin (delafloxacin) (delafloxacin) (levofloxacin) (moxifloxacin) (moxifloxacin) (gemifloxacin) (ciprofloxacin) (ciprofloxacin)

Acute bacterial sinusitis caused by Streptococcus pneumoniae, ∞ ∞ ∞ Haemophilus influenzae, or Moraxella catarrhalis. Acute bacterial exacerbation of chronic bronchitis caused by S. ∞ pneumoniae or H. influenzae. Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, H. influenzae, Haemophilus parainfluenzae, Klebsiella ∞ ‡ ∞ ╪ ∞ pneumoniae, methicillin-susceptible Staphylococcus aureus, or M. catarrhalis. Community acquired pneumonia caused by S. pneumoniae or H.  influenzae. Community acquired pneumonia caused by S. pneumoniae*, H. influenzae, M. catarrhalis, methicillin-susceptible S. aureus, K.  ‡‡ ∫ pneumoniae, Mycoplasma pneumoniae, or Chlamydia pneumoniae. Lower respiratory tract infections caused by Escherichia coli, K. pneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, H. influenzae, H. parainfluenzae, or penicillin-susceptible S.  pneumoniae.** Also, M. catarrhalis for the treatment of acute exacerbations of chronic bronchitis. Uncomplicated skin and skin structure infections caused by   methicillin-susceptible S. aureus or Streptococcus pyogenes. Uncomplicated skin and skin structure infections caused by  methicillin-susceptible S. aureus, S. pyogenes, or P. mirabilis. Complicated skin and skin structure infections caused by methicillin-  susceptible S. aureus, E. coli, K. pneumoniae, or E. cloacae. Complicated skin and skin structure infections caused by methicillin- susceptible S. aureus, S. pyogenes, Enterococcus faecalis, or P.  mirabilis. Skin and skin structure infections caused by E. coli, K. pneumoniae, E. cloacae, P. aeruginosa, methicillin-resistant and methicillin-susceptible  S. aureus, S. haemolyticus, S. lugdunensis, S. agalactiae, S. anginosus Group, S. pyogenes, and E. faecalis Skin and skin structure infections caused by E. coli, K. pneumoniae, E. cloacae, P. mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, P. aeruginosa, methicillin-susceptible S.  aureus, methicillin-susceptible Staphylococcus epidermidis, or S. pyogenes. Bone and joint infections caused by E. cloacae, Serratia marcescens,  or P. aeruginosa. Complicated intra-abdominal infections caused by E. coli, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, E. faecalis,  P. mirabilis, Clostridium perfringens, Bacteroides thetaiotaomicron, or

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Indication Cipro Avelox release Factive Levaquin Levaquin ofloxacin extended extended BAXDELA BAXDELA ciprofloxacin ciprofloxacin (delafloxacin) (delafloxacin) (levofloxacin) (moxifloxacin) (moxifloxacin) (gemifloxacin) (ciprofloxacin) (ciprofloxacin)

Peptostreptococcus species. Complicated intra-abdominal infections (used in combination with metronidazole) caused by E. coli, P. aeruginosa, P. mirabilis, K.  pneumoniae, or B. fragilis. Uncomplicated urinary tract infection (acute cystitis) caused by E. ∞ coli, P. mirabilis, E. faecalis, or Staphylococcus saprophyticus. Uncomplicated urinary tract infection caused by E. coli, K. ∞ pneumoniae, or S. saprophyticus. Complicated urinary tract infection caused by E. coli, P. mirabilis, K.  ╪╪ pneumoniae, E. faecalis, or P. aeruginosa. Complicated urinary tract infection caused by E. coli, P. mirabilis, K.  pneumoniae, P. aeruginosa, or Citrobacter diversus. Acute uncomplicated pyelonephritis caused by E. coli.   Urinary tract infection caused by E. coli, K. pneumoniae, E. cloacae, Serratia marcescens, P. mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter koseri (diversus), Citrobacter freundii, P. † aeruginosa, methicillin-susceptible S. epidermidis, S. saprophyticus, or vancomycin-susceptible E. faecalis. Acute uncomplicated cystitis in females caused by E. coli or S. ∞ saprophyticus. Acute uncomplicated cystitis caused by C.diversus, Enterobacter ∞ aerogenes, E. coli, K. pneumoniae, P. mirabilis, or P. aeruginosa. Chronic bacterial prostatitis caused by E. coli or P. mirabilis.  Chronic bacterial prostatitis caused by E. coli, E. faecalis or methicillin-  susceptible S. epidermidis. Prostatitis caused by E. coli.  Infectious diarrhea caused by E. coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii, Shigella dysenteriae, Shigella  flexneri or Shigella sonnei. Typhoid fever (enteric fever) caused by Salmonella typhi.  Uncomplicated cervical and urethral gonorrhea caused by Neisseria   gonorrhoeae. Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to aerosolized Bacillus ††  anthracis. Plague caused by Yersinia pestis (treatment and prophylaxis).  ††  Urethritis and cervicitis caused by Chlamydia trachomatis  Mixed infections of the urethra and cervix or pelvic inflammatory  disease due to N. gonorrhoeae and C. trachomatis. * Multi-drug resistant isolates

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∫ Also indicated for H. parainfluenzae and Legionella pneumophilia. Also indicated for nosocomial pneumonia caused by methicillin‑susceptible S. aureus, P. aeruginosa, S. marcescens, E. coli, K. pneumoniae, H. influenzae, or S. pneumoniae. Adjunctive therapy should be used as clinically indicated. Where P. aeruginosa is a documented or presumptive pathogen, combination therapy with an anti-pseudomonal β-lactam is recommended. ‡ Not indicated for K. pneumoniae or methicillin-susceptible S. aureus. ‡‡ Not indicated for methicillin-susceptible S. aureus. ╪ Not indicated for K. pneumoniae. ╪╪ Also indicated for E. cloacae. ** Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to S. pneumoniae. † Complicated urinary tract infections and pyelonephritis due to E. coli for children one to 17 years but not drug of first choice. †† For adults and children ∞ Reserve for use in patients who have no alternative treatment options.

(Prescribing information: Avelox, 2016; Baxdela, 2017; Cipro, 2016; Ciprofloxacin extended release tablet, 2016; Factive, 2016; Levaquin, 2017; Ofloxacin, 2016)

 Information on indications, mechanism of action, pharmacokinetics, dosing, and safety has been obtained from the prescribing information for the individual products, except where noted otherwise.

CLINICAL EFFICACY SUMMARY  The efficacy of the fluoroquinolones has been well documented in the treatment of genitourinary, respiratory, dermatological, and other miscellaneous infections, including typhoid fever and complicated intra-abdominal infections.  A meta-analysis demonstrated no significant differences in clinical or microbiological efficacy between the quinolones for the treatment of acute cystitis (Rafalsky et al, 2006). Another meta-analysis found no difference between fluoroquinolones and other classes of antibiotics for uncomplicated cystitis with regard to symptomatic cure (Zalmanovici-Trestioreanu et al, 2010). For the treatment of urinary tract infections, two randomized clinical trials were conducted that directly compared the once-daily, extended-release formulation of ciprofloxacin with the equivalent dose of the twice-daily immediate release formulation (Fourcroy et al, 2005; Talan et al, 2004). Overall, the extended-release formulation was found to provide comparable bacteriological eradication rates and/or clinical cure rates as the immediate-release formulation with comparable rates of adverse reactions.  Several head-to-head trials have demonstrated no significant differences between fluoroquinolone agents for the treatment of urinary tract infections (Arredondo-Garcia et al, 2004; Auquer et al, 2002; Peterson et al, 2008; Raz et al, 2000; Richard et al, 2008; Schaeffer et al, 1992). In one study, cefpodoxime did not demonstrate non-inferiority versus ciprofloxacin in the treatment of acute cystitis (Hooten et al, 2012).  Both levofloxacin and ciprofloxacin have demonstrated efficacy in the treatment of bacterial prostatitis (Bundrick et al, 2003; Naber et al, 2008). In a meta-analysis, no fluoroquinolone demonstrated consistent superiority over another for the treatment of chronic bacterial prostatitis (Perletti et al, 2013).  Four meta-analyses have been conducted comparing quinolones to other antibiotics for the treatment of acute sinusitis and community-acquired pneumonia (Karageorgopoulos et al, 2008; Salkind et al, 2002; Varadakas et al, 2008; Raz- Pasteur et al, 2015). Results from these analyses established the efficacy of the quinolones in respiratory infections. When compared to other antibiotics (β-lactams, macrolides, β-lactams/macrolide combination therapy, doxycycline, or a ketolide), treatment with quinolones was generally clinically comparable or superior. However, the majority of trials assessed in the meta-analysis by Salkind et al included sparfloxacin, trovafloxacin, and grepafloxacin, which are not currently available in the United States. In another meta-analysis, gemifloxacin was shown to have a higher treatment success rate than other fluoroquinolones and similar rates to β-lactams and macrolides in the treatment of community- acquired pneumonia and acute exacerbations of chronic bronchitis (Zhang et al, 2012). Eradication rates were similar between gemifloxacin and other fluoroquinolones, β-lactams, and macrolides.  A meta-analysis in patients with acute COPD exacerbations did not find a consistent significant benefit of antibiotics across outcomes with the exception of patients admitted to the intensive care unit (Vollenweider et al, 2012).  For patients with skin and skin structure infections, two trials demonstrated similar clinical success and eradication rates with levofloxacin and ciprofloxacin (Nichols et al, 1997; Nicodemo et al, 1998). Additionally, results from clinical trials Data as of June 21, 2017 PH-U/YP-U/KAL Page 4 of 8 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when making medical decisions.

have revealed similar cure rates for delafloxacin compared to tigecycline, linezolid, and the combination of vancomycin/aztreonam in the treatment of acute bacterial skin and skin structure infections (O’Riordan et al 2015; Kingsley et al, 2016; O’Riordan et al, 2016).  A meta-analysis of four randomized, controlled trials evaluated moxifloxacin versus other combination antibiotic regimens for the treatment of intra-abdominal infections (Mu et al, 2012). This analysis showed that moxifloxacin had similar clinical cure rates, bacteriological success rates, and mortality compared with those of the control group.

CLINICAL GUIDELINES  Treatment guidelines for the treatment of community-acquired pneumonia, urinary tract infections, skin and soft tissue infections, and vertebral osteomyelitis recommend fluoroquinolones as alternative agents (Berbari et al, 2015; Chow et al, 2012; Gupta et al, 2011; Mandell et al, 2007; Snellman et al, 2013; Stevens et al, 2014).  Fluoroquinolones should be considered first-line therapy for bacterial prostatitis, inhalational anthrax, and some types of infectious diarrhea (Guerrant et al, 2001; Stern et al, 2008).  The Centers for Disease Control and Prevention has determined that fluoroquinolones should no longer be used for the treatment of gonorrhea due to resistant organisms. They are not recommended for routine use in pelvic inflammatory disease unless antimicrobial susceptibility testing is performed and the fluoroquinolone will be administered in combination with metronidazole (CDC, 2015).

SAFETY SUMMARY  All fluoroquinolones carry a boxed warning for disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly observed adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (ie, hallucinations, anxiety, depression, insomnia, severe headaches, confusion). ○ The risk for fluoroquinolone-associated tendinitis and tendon rupture is increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart, or lung transplants.  Due to the potentially permanent serious adverse events involving the tendons, muscles, joints, nerves, and central nervous system, the FDA published a safety communication which recommends reserving the use of fluoroquinolones in acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections for patients with no alternative treatment options (FDA press release, 2016). A subsequent safety alert released by the FDA stated that after review, it did not find that use of fluoroquinolones resulted in detached retina, aortic aneurysm, or aortic dissection (FDA press release, 2017).  Fluoroquinolones may cause QT interval prolongation, anaphylactic reactions, phototoxicity, Clostridium difficile diarrhea, blood glucose disturbances. Additionally, fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis and should therefore be avoided.  The most common adverse events with fluoroquinolones include gastrointestinal (eg, nausea, vomiting, diarrhea) and central nervous system (eg, dizziness, headache) toxicities. Rash is frequently observed with fluoroquinolones and is especially common with gemifloxacin.  All fluoroquinolones bind to multivalent cations. Administration of a fluoroquinolone should be separated by at least two hours from products containing aluminum, magnesium, iron, or zinc.  Additional drug interactions include Class IA and Class III antiarrhythmics, nonsteroidal anti-inflammatory drugs, phenytoin, probenecid, sulfonylureas, theophylline, tizanidine, and warfarin.  Oral dosing of ciprofloxacin, gemifloxacin, levofloxacin, and ofloxacin should be adjusted in renal impairment. Delafloxacin is not recommended for use in patients with end stage renal disease. The daily dose of ofloxacin should not exceed 400 mg in patients with severe liver dysfunction.

DOSING AND ADMINISTRATION Table 3. Dosing and Administration Usual Available Drug Route Recommended Comments Formulations Frequency Avelox (moxifloxacin)*,† Tablet Oral Every 24 hours Baxdela (delafloxacin)* Tablet Oral Every 12 hours Not recommended in ESRD (eGFR <

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Usual Available Drug Route Recommended Comments Formulations Frequency 15 including hemodialysis) Cipro (ciprofloxacin)*,† Tablet, suspension Oral Every 12 hours Oral dose adjustments are ciprofloxacin extended release Tablet Oral Every 24 hours recommended in renal impairment. Factive (gemifloxacin) Tablet Oral Every 24 hours Ofloxacin dose should not exceed 400 Levaquin (levofloxacin)* ,† Tablet, oral solution Oral Every 24 hours mg per day in patients with severe † ofloxacin Tablet Oral Every 12 hours liver dysfunction disorders. Abbreviations: eGFR = estimated glomerular filtration rate; ESRD = end stage renal disease * Also available as intravenous solution † Also available as otic and/or ophthalmic formulations See the current prescribing information for full details

CONCLUSION  Fluoroquinolones have a broad spectrum of activity and may be used to treat a variety of infections. Current clinical evidence supports the efficacy of all products in this class for their FDA-approved indications, and efficacy appears comparable among agents. No fluoroquinolone has consistently demonstrated superiority over another.  Fluoroquinolones should be considered first-line therapy for bacterial prostatitis, inhalational anthrax, and some types of infectious diarrhea (Stern et al, 2008; Guerrant et al, 2001). ○ Treatment guidelines recommend fluoroquinolones as alternative agents for the treatment of community-acquired pneumonia, urinary tract infections, skin and soft tissue infections, and vertebral osteomyelitis (Berberi et al, 2015; Gupta et al, 2011; Mandell et al, 2007; Solomkin et al, 2010; Stevens et al, 2014). They are not generally recommended for the treatment of bacterial sinusitis (Chow et al, 2012; Snellman et al, 2013). The Centers for Disease Control and Prevention has determined that fluoroquinolones should no longer be used for the treatment of gonorrhea due to resistant organisms (CDC, 2015).  All fluoroquinolones share a boxed warning for disabling and potentially irreversible serious adverse reactions such as tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (ie, hallucinations, anxiety, depression, insomnia, severe headaches, confusion). Due to the risk for permanent adverse effects, the FDA warns that fluoroquinolones should be reserved for patients with no other treatment options when used to treat acute sinusitis, acute bronchitis, and uncomplicated urinary tract infections (FDA press release, 2016).  Additional warnings for the class include QT prolongation, blood glucose disturbances, Clostridium difficile-associated diarrhea, and phototoxicity. Fluoroquinolones should be avoided in patients with a history of myasthenia gravis.

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Data as of June 21, 2017 PH-U/YP-U/KAL Page 6 of 8 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when making medical decisions.

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Data as of June 21, 2017 PH-U/YP-U/KAL Page 7 of 8 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when making medical decisions.

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Publication Date: June 27, 2017

Data as of June 21, 2017 PH-U/YP-U/KAL Page 8 of 8 This information is considered confidential and proprietary to OptumRx. It is intended for internal use only and should be disseminated only to authorized recipients. The contents of the therapeutic class overviews on this website ("Content") are for informational purposes only. The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Patients should always seek the advice of a physician or other qualified health provider with any questions regarding a medical condition. Clinicians should refer to the full prescribing information and published resources when making medical decisions.